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Neurobiol Stress. 2019 Sep 27;11:100196. doi: 10.1016/j.ynstr.2019.100196. eCollection 2019 Nov.

Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond.

Zorumski CF1,2,3, Paul SM1,4,3, Covey DF1,5,3, Mennerick S1,2,3.

Author information

1
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
2
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA.
3
The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA.
4
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
5
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.

Abstract

The recent FDA approval of the neurosteroid, brexanolone (allopregnanolone), as a treatment for women with postpartum depression, and successful trials of a related neuroactive steroid, SGE-217, for men and women with major depressive disorder offer the hope of a new era in treating mood and anxiety disorders based on the potential of neurosteroids as modulators of brain function. This review considers potential mechanisms contributing to antidepressant and anxiolytic effects of allopregnanolone and other GABAergic neurosteroids focusing on their actions as positive allosteric modulators of GABAA receptors. We also consider their roles as endogenous "stress" modulators and possible additional mechanisms contributing to their therapeutic effects. We argue that further understanding of the molecular, cellular, network and psychiatric effects of neurosteroids offers the hope of further advances in the treatment of mood and anxiety disorders.

KEYWORDS:

Allopregnanolone; Brexanolone; SGE-217; Steroid enantiomers; Tonic inhibition

Conflict of interest statement

CZ and SP are members of the Scientific Advisory Board of Sage Therapeutics and CZ, SP and DC have stock in Sage Therapeutics. Sage Therapeutics was not involved in writing or review of this manuscript.

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